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Toxicological information

Repeated dose toxicity: other routes

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Administrative data

Endpoint:
chronic toxicity: other route
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: pre-guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1967
Report date:
1967

Materials and methods

Test guideline
Qualifier:
no guideline available
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Automatically generated during migration to IUCLID 6, no data available
IUPAC Name:
Automatically generated during migration to IUCLID 6, no data available
Details on test material:
- Name of test material (as cited in study report): gestonorone caproate

Test animals

Species:
rat
Strain:
other: JCL-SD
Sex:
male/female

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
castor oil
Remarks:
with benzyl benzoat
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 weeks
Frequency of treatment:
once weekly
Doses / concentrations
Remarks:
Doses / Concentrations:
0 - 5 - 25 - 125 mg/kg
No. of animals per sex per dose:
20/sex/group
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
NOEL
Effect level:
< 5 mg/kg bw/day
Based on:
not specified
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Increased bw and food consumption in females at the mid dose and higher.

Dose-dependent effects on prostate (decreased weights, slight atrophy), ovary (decreased weight, atrophy, cystic follicles, disappearance of corpus luteum), vagina (vacuolation) and uterus (decreased weights, light to severe atrophy, disappearance of uterine gland, papillomatous hyperplasia of endometrium and nodular hyperplasia of longitudinal muscle layer) at 5 mg/kg; seminal vesicle (decreased weights, atrophy) at 25 mg/kg, and in addition on testis (reduced weight) at 125 mg/kg. Two fibroadenoma without a dose-dependency in one female each at the doses of 5 and 25 mg/kg

Applicant's summary and conclusion

Conclusions:
Based on the results there is no classification required according to Directive 67/548/EEC
Executive summary:

No repeat-dose studies were conducted with ZK 5686 (gestonorone). Results of studies conducted with an ester of gestonorone (gestonorone caproate, ZK 5623) are regarded as representative as most likely ester cleavage occurs in vivo after administration.

The subcutaneous, once weekly administration of ZK 5623 to rats at doses of 5, 25 and 125 mg/kg over 28 weeks resulted in increased body weight gain and food consumption in females at the mid dose and higher. Post mortem examination revealed the expected exaggerated pharmacodynamic effects of a gestagen from the lowest tested dose upwards and include dose-dependent effects on prostate (decreased weights, slight atrophy), ovary (decreased weight, atrophy, cystic follicles, disappearance of corpus luteum), vagina (vacuolation) and uterus (decreased weights, light to severe atrophy, disappearance of uterine gland, papillomatous hyperplasia of endometrium and nodular hyperplasia of longitudinal muscle layer) at 5 mg/kg; seminal vesicle (decreased weights, atrophy) at 25 mg/kg, and in addition on testis (reduced weight) at 125 mg/kg. No clear signs of organtoxicity were observed. Two fibroadenoma were detected without a dose-dependency in one female each at the doses of 5 and 25 mg/kg. The NOEL is < 5 mg/kg after once weekly subcutaneous administration.